1,3-ethanoindeno(2,1-c)-pyridines and 1,3-ethanobenz(g)isoquinolines

ABSTRACT

Compounds of the 1,3-ethanoindeno(2,1-c)pyridine and 1,3ethanobenz(g)isoquinoline series, having local anesthetic and analgesic activity, are prepared by acid cyclization of 3-aryl or 3-arylmethyltropane-2-carboxylic acids or their esters.

United States Patent 1 Clarke et al.

[451 Aug. 26, 1975 1,3-ETHANOIN DENO[ 2,1-C ]-PYRIDINES AND l,3-ETHANOBENZ[G )ISOQUINOLINES Inventors: Robert L. Clarke, Bethlehem; Sol J.

Daum, Albany, both of NY.

Assignee: Sterling Drug Inc., New York, N.Y.

Filed: Dec. 14, 1973 Appl. No.: 424,882

U.S. CI...H. 260/283 R; 260/287 R; 260/289 R; 260/292; 260/999 Int. Cl. C07D 451/02 Field of Search 260/283 R, 287 R, 289 R, 260/293.54, 292

References Cited UNITED STATES PATENTS 8/]969 Paragamian et al. 260/294 3,499,895 3/[970 Jucker et al. 260/2475 Primary ExaminerG. Thomas Todd Attorney, Agent, or Firm-Thomas L Johnson; B. Woodrow Wyatt [57] ABSTRACT 30 Claims, No Drawings 1.3-ETHANOINDENOD .l -c]-PYRI DIN ES AN D 1,3-ETH ANOBENZBHSOQU INOLINES This invention relates to novel compounds wherein a benzocycloalkane moiety is fused to the ZJ-position of a tropane nucleus. More particularly. the invention is concerned with compounds of the l .3- cthanoindenol 2. l -c ]pyridine and l .3- ethanobenz[glisoquinoline series and with methods for the preparation thereof.

The compounds of the invention are of the following formula:

I. ll

wherein:

R is hydrogen. lower-alkyl, lower-alkanoyl. loweralkoxycarbonyl. cycloalkylcarbonyl, cycloalkyllower-alkyl. phenyl-lower-alkyl or hydroxy-loweralkyl; C=Z is C=O. CH CH(OH) or CH(O-loweralkanoyl);

Any stcreochemical arrangement of the tropane nucleus and substituent groups is contemplated. although the configuration of the natural belladonna type alkaloids. atropine. cocaine. etc. is preferred The com pounds of the invention, if derived by synthesis from the natural sources will be optically active. However. optically inactive raceniic mixtures can be obtained by total synthesis and these in turn can be resolved by conventional procedures to obtain both optical isomers. one being identical with the enantiomer obtained from natural sources and the other the unnatural" enantiomer.

The term lower-alkyl" in the above definitions of R and the phenyl substituents stands for alkyl having from one to six carbon atoms which may be straight or branched. preferably primary or secondary, thus including methyl, ethyl. propyl isopropyl. butyl. sec.- butyl, pentyl. hexyl and the like.

The term lower-alkoxy" in the above definition of the phenyl substituents stands for alkoxy having from one to four carbon atoms which may be straight or branched, preferably primary or secondary. thus including methoxy, cthoxy, propoxy. isopropoxy. butoxy. secondary-butoxy. isobutoxy and tertiary-butoxy.

The term lower-alkoxy" in the above definitions of R. C=Z and phenyl substituents stands for alkanoyl having from one to six carbon atoms which may be straight or branched, thus including formyl. acetyl. propionyl. butyryl. isobutyryl. valeryl, caproyl. and the like.

The term cycloalkyl" in the above definition of R stands for cycloalkyl having from three to six ring members and a total carbon content of from three to ten carbon atoms. thus including cyclopropyl. cyclobutyl. cyclopentyl and cyclohexyl; and lower-alkylated derivatives thereof. cg. Z-methylcyclopentyl. 4- butylcyclohexyl and the like.

The compounds of formula I wherein C=Z is C=O are prepared by cyclization of compounds of the formula:

l N-R C-(CH Ar wherein R and n have the meanings given above. R' is hydrogen or lower-alkyl. and Ar is phenyl or phenyl substituted by from one to two substituents selected from the group consisting of lower-alkyl, loweralkoxy. fluoro, chloro and hydroxy. The cyclization is effected by heating a compound of formula II with an acidic catalyst at a temperature between about 75C. and 200C. A preferred catalyst is polyphosphoric acid and a preferred temperature range is l00-l50(.

The starting materials of formula ll where R and R are lower-alkyl and n is U are prepared from an anhydroecgonine lower-alkyl ester and an Ar-magnesium halide as described in our copending application Scr. No. 306.918. filed Nov. l5. 1972. now US. Pat. No. 3,813,404. The compounds of the formula ll where R is hydrogen are prepared by hydrolysis of the esters (R' is lower-alkyl); and the compounds of formula ll where R is other than lowcr-alkyl are prepared by chemical manipulations of the nitrogen substituent as described below. 'I he compounds of formula ll where u is l are prepared analogously by reacting an anhydroecgonine lowcr-alkyl ester with an ArCH -magnesium halide Cyclization of the compounds of formula II where n s provides compounds of the formula IA when the :yclopentanone ring is fused to the tropane nucleus in he cis manner. that isomer having the thermodynamcally preferred configuration. In such a configuration. he carbonyl group at C9a has an axial configuration .nd therefore should block quaternization of the nitro- ;cn atom. In accordance with this prediction it was ound that the compounds of formula IA where (=2 is i=0 failed to react with ethyl iodide.

Cyclization of the compounds of formula II where n s l provides compounds of formula IB as a mixture of somers where the cyclohexanone and tropanc moieties ire fused in the cis and trans manner labsolute configuations (natural) lR.3S.4aS.lUaS; and lR.3S,4aS,l- IaR. respectively].

The compounds of formula I where C=Z is (=0 can )0: converted to compounds where C=Z is CH(OH) ind CH Conversion of the ketones to the correspondng thioketals followed by desulfurization with Raney iickel affords the compounds where C=Z is CH Reluction of the ketones with sodium borohydride proluces epimcric mixtures of alcohols [C=Z is CH(()- IB) and CH(OHa)]. Reduction of the ketones vith diborane results in formation of mixtures of the :pimeric alcohols [C=Z is CH(OH)] and methylene lerivatives (C=Z is CH;). The proportion of products n the mixture depends upon reaction conditions and iature of the aryl substituents. For example. the pres- :nce of a mcthoxy group in the 6- or 8-position of the :ompounds of formula IA activates the 9-position with he result that reduction of the carbonyl group at C-9 :ffects complete reduction to methylene (C=Z is CH vith no intermediate alcohols being detected. Reducion of the ketones with Adams platinum oxide catalyst iffords mixtures of the epimeric alcohols [C=Z is H(OH)I The compounds of formula I where C=Z is CH(()- ower-alkanoyl) are prepared by conventional csterifr ration reactions with the appropriate acid anhydride or icid halide.

When the alcohols of formula I [C=Z is CH(()H)) ire heated with phosphorus oxychloride. dehydration .akes place. In the indenopyridine series (formula IA) 1 double bond forms in the 9.9aposition which upon LICLIIIITICI'II with base rearranges to the 4a.9a-position. Iydrogenation of compounds of formula IA. wherein here is a double bond in the 9.9a-position with palladiim-on-carbon affords compounds of formula IA .vherein C=Z is CH; and having a cis-syn configuration. wherein the aromatic ring is on the same side of the nolccule as the nitrogen atom. On the other hand, simlar hydrogenation of compounds of formula IA vherein there is a double bond in the 4a.Ja-position af- 'ords compounds of formula IA wherein (=2 is CH: ind having a cis-ariti configuration. wherein the aronatic ring is on the opposite side of the molecule from he nitrogen atom.

The compounds of formula I where the phenyl ring s substituted by hydroxy are readily prepared by acid :leavage. e.g. with hydrogen bromide. or the corre iponding methoxy compounds. In fact. when com- )ounds of formula II (R' lower-alkyl) bearing a 4- nethoxy group in the aromatic ring are treated with Jolyphosphoric acid at l50C.. ether cleavage occurs luring the cyclilation. giving the corresponding hy- Jroxy compound of formula I. It is possible. however.

(iii

to avoid ether cleavage during cyclization by using as a starting material the corresponding carboxylic acid of formula II (R'=H) which cycli7es at a lower temperature.

The compounds of formula I wherein R is hydrogen can be prepared from the compounds of formula I wherein R is methyl by demethylation procedures. The N-methyl compounds react with a lower-alkyl chlorocarbonate to form the corresponding urethane com pounds wherein R is lower-alkoxycarbonyl. The latter undergo acid hydrolysis to give the compounds of for mula l where R is hydrogen. Alternatively. the N- methyl compounds are treated with 2-chloroethyl chloroform-ate. followed by reacting the resulting N-( Z-chloroethoxycarbonyl) compound with chronious perchlorate.

The compounds of formula I wherein R is hydrogen undergo various reactions to form N-substituted derivatives. Lower-alkanoic acid chlorides. cycloalkariecarboxylic acid chlorides. cycloalkane-lower-alkanoic acid chlorides. benzoyl chloride. or phenyl-loweralkanoic acid chlorides react with the compounds of formula I wherein R is hydrogen to form the corresponding N-lowenalkanoyl. N-cycloalkylcarbonyl. N-cycloalkyl-lower-alkanoyl. N-benzoyl or N-phenyllowcr-alkanoyl compounds. respectively. The soobtained amides can be reduced with lithium aluminum hydride to form N-lower-alkyl. N-cycloalkyl-loweralkyl and N-phenyl-lower-alkyl compounds. The compounds of formula I wherein R is hydrogen also can be caused to react with a hydroxy-lower-alkyl halide under alkaline conditions to give compounds of for mula I wherein R is hydroxy-lower-alkyl.

Pharmacological evaluation of the compounds of formula I has shown that they possess local anesthetic activity when tested by the standard intradermal anesthetic test in guinea pigs [Bulbring and Wajda. J. Pharmacol. Exptl. Therap. 85. 78 l945)l. The compounds have an activity ranging from about 20 to about percent that of cocaine. Furthermore. the compounds have been found to be active in the prevention of abdominal constriction in mice by acetylcholine {Collier et al.. Brit. J. Pharmacol. Chemother. 32. 295 l968)| or by phenyl-p-benzoquinone [Pearl et a].. I. Pharmacol. Exptl. Therap. 154. 3l9 (1966)]. which are standard tests indicative of analgesic activity.

The compounds of formula I which are secondary or tertiary amines and thus are basic in character are useful both in the free base form and in the form of acidaddition salts. and both forms are within the purview of the invention. The acid addition salts are simply a more convenient form for use. and in practice use of the salt form inherently amounts to use of the base form. For pharmaceutical purposes. the acids which can be used to prepare the acidaddition salts include preferably those which produce. when combined with the free base. medicinally acceptable salts. that is. salts whose anions are relatively innocuous to the animal organism in medicinal doses of the salts. so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions. Appropriate medicinally acceptable salts within the scope of the invention are those derived from mineral acids such as hy drochloric acid. hydrobromic acid. hydriodic acid. nitric acid. phosphoric acid. sulfamic acid. and sulfuric acid; and organic acids such as acetic acid. citric acid. tartaric acid. lactic acid. cyclohexanesulfamic acid.

methanesulfonic acid. cthanesull'onic acid. benzenesulfonic acid. p-toluenesullbnic acid. quinic acid. and the like. giving the hydrochloride. hydrobromide. hydriodide. nitrate. phosphate. sulfamate. acetate. citrate. tartrate. lactate. cyclohexancsullamate. methancsul ton-ate. ethanesultonate. henzenesulfonate. [Holucnesulfonatc and quinate. respectively.

The acid-addition salts of said basic compounds are prepared either by dissolving the free base in aqueous or aqueousalcohol solution containing the appropriate acid and isolating the salt by evaporating the solution. or by reacting the free base and acid in an organic solvent. in which case the salt separates directly or can be obtained by concentration of the solution.

Although medicinally acceptable salts of said basic compounds are preferred for pharmaceutical purposes. all acid-addition salts are within the scope of our inven tion. All acid-addition salts are useful as sources of the free base form even it the particular salt per se is desired only as an intermediate product as for example when the salt is formed only for purposes of purifica tion or identification. or when it is used as an intermediate in preparing a medicinally acceptable salt by ion exchange procedures.

The compounds can he prepared for use by dis solving under sterile conditions salt forms of the compounds in water (or an equivalent amount of non-toxic acid if the free base is used). or in a physiologically compatible aqueous medium such as saline. and stored in ampoules for intramuscular injection. Alternatively. they can be incorporated in unit dosage form as tablets or capsules for oral administration either alone or in combination with suitable adjuvants such as calcium carbonate. starch. lactose. talc. magnesium stearate. gum acacia. and the like.

The molecular structures of the compounds of this invention were assigned on the basis of the methods of their synthesis and the study of their infrared and nuclear magnetic resonance (NMR) spectra. and confirmed by the correspondence between calculated and found values for the elementary analyses for representative examples.

The best modes of carrying out the preparative aspects of the invention are as follows:

EXAMPLE I lR.3S.4aS.9aS l .2.3.4.4a.9a-Hexahydro-Z-methyl- 9H-l.3-ethanoindcnolll-clpyridin-Q-onc llA; C=Z is C=O, R is CH A l:} mixture of methyl (lR.ZS.3S.5S)-3B-phenyllaH.501H-tropane-Z/i-carboxylate and its Za-epimer. methyl llR.2R.3S.5S)-3/3phenyl-laHfiozH-tropane- Za-carboxylate (370 g.. L42 mol) was warmed to 100C. and added all at once to 3.7 kg. (ll mol) of polyphosphoric acid at l(l()(. with stirring. This mixture was stirred at 150C. for 5 hours and poured onto a large volume of crushed ice. Concentrated ammonium hydroxide (5.4 kg.) was added with cooling and the alkaline mixture was extracted with methylene di chloride. The dried (sodium sulfate) extracts were concentrated to give an oily residue which was extracted with a total of 8 liters of pentane. Part of the pent-tine was distilled off and there precipitated 136 g. ot'( lR.3- S.4aS.9aS)'l1.3.4.4a.911hcxahydro2-methyl-9Hl.3- ethanoindenol ll -c]pyridin-)-one. m.p. 7578(. lhc mother liquor residue in 500 ml. of methanol was added to a solution ol 4-H) g. of sodium metabisull'ite (at l (Na s- 0 in 2.2 liters of water. Extraction of this solution with 6 X 500 ml. of methylene dichloride separated 3] g. (8% of starting material. The aqueous solution together with some bisulfite adduct which had precipitated was treated with 560g. of solid sodium bicarbonate. Water (200 ml.) and methylene dichloride 1.] liters) were added and the mixture was heated under re Flux for 5 hours. The methylene dichloride layer yielded a solid residue which was recrystallized from pentane. giving 85.2 g. more of lR.3S.4aS.9aS)- l.13.4.4a.9a-hexahydro-Z-methyl-QH-l.3-ethanoindeno[2.l-c]pyridin-'-)-one. m.p. 78C. [76% based on methyl lR.2S.3S.5S)-3B-phenyl-laH.5aH- tropane-2B-carboxylate consumed]. Further recrystallization gave a sample melting at 7879C.; [a],, +134".

The hydrochloride salt of lR.3S.4aS.9aS l.2.3.4.4a.9ahexahydro-2methyl-9H-l .3-ethanoindeno[2.l-c Ipyridin-9-one when recrystallized from acetonitrile showed polymorphism. m.p. 222224C and 259C. (dcc. cvac. cap. la],,'-''-=+39.8{ l /r in H O).

lR.3S.4aS.9aS)- l .23.4.4a.9a-Hexahydro-Z-methyl- 9H-l .B-ethanoindenol2.1-clpyridin-9-one failed to react with ethyl iodide in ether solution at room temperature. This observation is consistent with the absolute configuration assigned.

By replacement of the BB-phenyl-lozH.5aH-tropane- 2carboxylate in the foregoing example by a molar equivalent amount of methyl S-isopropyl Ilfi-phenyll01H.5aH-nortropane-2-carboxylate. methyl 3B-(pchlorophenyl l 04H.5txH-tropane-Z-carboxylate. methyl 3B-( 3.4-dimethoxyphenyl laHfiaH-tropanelearboxylate. methyl 3B-( 3-methoxy-4 chlorophenyl l 01H.5ozHtropaneZ-carboxylate. or methyl 3/3-( 4-methylphenyl laHfiaH-tropane-IL carboxylate. there can be obtained. respectively.

1 .2.3.4.4a.9a-hexahydro-Z-isopropyl )H-[.3-

l .13.4.4a. a hexahydro-lmethyl-7-chloro-9H- l .3-

ethanoindeno-l2.l-c]pyridin-9-one HA; C=Z is C 0. R is CH;,. 7-Cll. l2.3.4.4a.9a-hexahydro-2-methyl-6.idimethoxy-QH- l.3-ethanoindenol2.l-c]pyridin-9-one [lA; C=Z is C=O. R is CH;., 6.7-(()CH;,) l.23.4.4a,9a-hexahydro-2methyl6 methoxy-7- chloro-9H l .3-ethanoindenol 2. l -c ]pyridin 9-one llA; C=Z is C=O. R is CH,. 6-OCH;.. 7 Cl].

l.2.3.4.4a.9a-hexahydro-2.7-dimethyl-9H- l .3-

[IA; C=Z is ethanoindenol 2. l -c l-pyridin-Q-one C=O. R is CH;,. 7CH;,].

EXAMPLE 2 lSJRAaRHaR )-l 2.3.4.4a.9a-Hexahydro-Z- methyl-)H-l .3-cthanoindenol 2. l -c ]pyridin-9-one (enantiomer of compound of Example I) was prepared rom a 1:3 mixture of methyl (lS.2R.3R.5R]-3/3- ihenyl-laH.5ozH-tropane-2B-carhoxylate and methyl lS.2S.3R.SR)-3B-phenyll aHfiaH-tropane-Za- :arboxylate according to the procedure of Example l. [he free base melted at 78-8()C. (from n-pentane); 01],, l 3.6", and the hydrochloride salt when crysallized from acetonitrile exhibited polymorphism. m.p. ll 822()C. and 261C. (dee). [al,, "=39.4 W: in 1 EXAMPLE 3 (lR.3S.4aS.9aS l .2,3.4,4a.9a-Hexahydro-Z-methyl- -fluoro-QH-l .B-ethanoindenol 2. l -c lpyridin-J-one IA'. C=Z is C=O. R is CH 7-F] was prepared from nethyl 334 p-fluorophenyl l aH.5ozH-tropane-2aand ZB-carboxylates and polyphosphoric acid according to .he procedure of Example l and obtained in 70% yield; iydrochloride salt. m.p. 285C. (dec. massive prisms 'rom acetonitrile'. [04],, =+36.2 l7r in H O).

EXAMPLE 4 lR.3S.4aS.9aS l 2.3,4.4a.9a-Hexahydro-Z-methyl- 7-methoxy-9H-l .3-ethanoindeno[ 2. l -c ]pyridin-9-one IA'. C=Z is C=O. R is CH 7-OCH was prepared "rom 3fi-( p-methoxyphenyl l aH .SaH-tropane-Z- :arboxylic acid (in turn prepared from the correspond- .ng methyl ester by 2 l-hr. reflux with 6 equivalents of 2N hydrochloric acid) and polyphosphoric acid heated .m a steam bath for 4 hours. The product was dissolved in hot benzene, decolorizcd with activated charcoal. .lnd crystallized upon cooling; yield 299? colorless nee' .lles. m.p. l(l7l()8.5(. (from hexane). [01],? 22.5 (1% in CHCl EXAMPLE 3B-(m-Methoxyphenyl)-lozH.5aH-tropane-2- carboxylic acid and polyphosphoric acid according to Example 4 gave a mixture of products which was chromatographcd on X 40 cm prep silica plates (0.25 g. per plate) using 3 solvent passes of isopropylamineether (3:97 The lead band afforded the free base of (lR.3S,4aS.9aS)- l .13.4.421.9a-hexahydro-Z-methyl-fimethoxy-9H-l .3-ethanoindeno[ 2.1 -c]pyridin-9-one HA; C=Z is C=O. R is CH,, (t-OCHsL mp. 92.594.5C in 4371 yield; hydrochloride salt. mp. 2 l 3-2l5C. (dec. colorless massive prisms. [01],? 7 +754 1% in H O). A trailing band on the chromatograph afforded l R.3S,4aS,9aS)-l .2.3.4.4a.9ahexahydro-2-methyl-8-methoxy-9H- l .3-ethanoindeno- [2,l-c1pyridin-9-one [IA; C=Z is C=O. R is (H 8- OCH in 13 percent yield. free base. colorless needles from tetrahydrofuran, mp. l43l45C.-, [01],, l5.8 l7: CHCl EXAMPLE (1 a. Methyl (lR.2RS.3S.5S)-3/3-benzyl-laH.5rxH- tropane-Zaand ZB-carhoxylate III; R and R are CH Ar is (1H n is l].

Benzylmagnesium chloride was prepared from 1 12 g. (0.74 mol) of benryl chloride and 26.8 g. l.l g. atom) of magnesium turnings in 75U ml. of ether and chilled to ?.0C. A solution of 710g. (().4() mol) of ()-anhydroecgonine methyl ester in 375 ml. of ether was added with stirring at -2U to 25C over a 3i) minute period. and the mixture was stirred at this temperature for 15 minutes. Ice and water (about 200 ml. were added fol lowed by ZN hydrochloric acid to acidity and dissolu tion of all solid. The layers were separated and the water layer washed with ether. The water layer was made basic with concentrated ammonium hydroxide and extracted 4 times with ether. The dried sodium sulfate extracts were concentrated and the residual oil (86.7 g.) was distilled. the product being collected at l43-]S2C. ((1.8 to (L6 mm) 36.7 g. (34%). in, l.53l7.

By replacing the benzyl chloride in the foregoing preparation by a molar equivalent amount of pfluorobenzyl chloride. p-chlorobenzyl bromide. pmethoxybenzyl chloride or p-methylbenzyl chloride. there can be obtained. respectively. methyl IR.2RS.3- $.55 )-3B-( p-fluorobenzyl l aH.SozH-tropane-2- earboxylate. methyl (lR,2RS.3S.5S)-3B-( pchlorobenzyl l aI-I.SaH-tropane-2-carhoxylate. methyl lR.2RS.3S.5S)-3B-(p-methoxybenzyl l01H.5aH-tropane-Z-carboxylate. or methyl (1R.2RS.- 35.55 )-3B-( p-methylbenzyl )-l ozH.5aH-tropane-2- carboxylate.

b. (lR,3S,4aR.l()aR)- l .3.4.4a.5. lllaHexahydro-l methyll .3-ethanobenzl glisoquinolinl 2H )-one [18; C=Z is C=O. R is Ch was prepared from 84 g. [0.031 mol) of the product of part (a) above and 58 ml. of polyphosphoric acid at I5UC for 5 hours. The oily product was distilled to give 4.5 g. of l R.3S.4aR lUa- R )-1 .3.4.4a.5 l()a-hexahydro-Z-methyl-l .3- ethanobenzlglisoquinolin-10(2H)-one as an amber oil. b.p. l36146C. HHS-0.2 mm.). n,,'-"" 1.5744; hydrochloride salt. mp 239240C. (colorless prisms from acetone). [01],, l l.7 l/( in H O).

By replacing the methyl IR.ZRS.3S.5S)-3[3ben2y1- l01H,5aHtropane-Z-carboxylate in the foregoing preparation by a molar equivalent S) of methyl (1 R.2RS, 3S,5S)-3B-(p-fluor0benzyl)-I aH,5aH-tropane-2- carboxylate. methyl (lR.2RS.3S SS )-3B(pchlorobenzyl l cxH,5uH-tropane-Z-carhoxylate. methyl (IR.2RS.3S.5S )-3B(pmethoxyben2yl laH.5aH'tropane-2-carboxylate. or methyl (IR.ZRS.- 3S.5S]-3B-(panethylbeiwyl)-laH.5xH-tropane-Z- carhoxylate. there can be obtained. respectively.

tlR.3S.4aR,I()aR)-l.3.4 4a.5,lUa-hexahydroimethyl-X-fluoro- I .3-ethanoben/.[ glisoquinolinel()(2H)-one [1B1 C=Z is C O. R is CH;.. B-FI.

(lR.3S.4aR. l (laR)-l .3.4.4a,5.l()a-hexahydro-Z- methyl-R-chlorol .3-ethanobenz[ glisoquinolinlt)(2I-I)-one [IB; C=Z is C=O, R is CH R-Cl lR.3S.4aR.l(laR)-1.3.4.4115. l(la-he\ahydro2 methyl-X-methoxyl .3-ethanobenz[ g )isoquinolin- I U (2H)one [I81 1 is C=O. R is (H;,. H-OCH or (lR.3S.4aR l()aR)- l 3.4.4215.llla-hexahydro-lii dimethyll ,3-ethanoben7i glisoquinolinllll 2H )-one IIB; C=Z is C=0. R is CH X-CH EXAMPLE 7 lR.3S.4aS.9aS J- l .2.3.4.4a.9a-Hexahydro-Z-methyl- 9H- l .3ethanoindenol 2.l-c lpyridine IIA1C=Z is CH R is CH;,].

A solution (W935 g. (H.040 mol olketone lR.?-S.-1- aS.9aS )l .23.4.-la.9a-hc\ahydro-Z-|iiethyl-)H- l .3- ethanoindeno-l 2,!-clpyridin- )-one in 250 ml. olaeetic acid was treated with 30 ml. of ethanedithiol and 20 ml, of boron trifluoride-etheratc. The next day the precipitate was separated. ether as added to the filtrate and more solid was collected. 'lhc solid residues were washed with fresh ether and then dissolved in water.

9 Dilute sodium hydroxide (2N) was added and the free base was separated with ether. Crystallization from pentane gave 6.7 g. (55%) of (1R.3S.4aS.9aSl-9.9- ethylenedithio-l .2.3.4.4a.9a-hexahydro-Z-methyl-QH- 1.3-ethanoindeno[2.l-clpyridine. m.p. if-103C.

Without further purification this product was dissolved in 350 ml. of 957: ethanol and refluxed for 12 hours in the presence of 12 teaspoonfuls of Rancy nickel. Removal of catalyst and solvent gave 3.4 g. of crude product. A portion ((1.5 g.) was chromatographed on silica prep plates (ether-pentaneisopropylamine. S():47:3) to give pure 1R.3S.4aS.9aS- )-1.2.3.4.4a.9a-hexahydro-2-methyl-9H-l .3- ethanoindeno[2.l-c]pyridine as an oil.

The remainder of the crude product was converted to the hydrochloride salt. 2.4 g.. mp. 301C. (dec.) from acetone. [a],,'-""= +935 1% in H O); total yield 517: from thioketal.

By the same procedure. l.2.3.4.4a.9a-hexahydro-2- isopropyl-9H-1.3-ethanoindeno[2.l-c]pyridin-9-one 1.2.3 .4.4a.9a-hexahydro-2-methyl-7-chloro-QH-1.3- ethanoindeno[2.1-c]pyridin-9-0ne. 1.2.3.4.4a.9ahe xahydro-2methyl-6.7-dimethoxy-9H- l .3-ethanoindeno[2.1-clpyridin-9-one. 1.2.3 .4.4a.9a-hexahydro-2- methyl-6'methoxy-7-ch1oro-9H-l.3-ethanoindeno[2.1- c lpyridin-Q-one. or 1.2.3 .4.4a.9a-hexahydro-2.7- dimethyl-QH-l .3-ethanoindeno[ 2. l -c]-pyridin-9-one can be reduced. respectively. to produce [.2 .3.4.4a.9a-hexahydro-2-isopropyl-9H-1.3-ethan0indeno[2.1-c]-pyridine []A'. C=Z is CH R is :i)2l- 1.2 .3.4.4a.9a-hexahydro-2-methyl-7-chloro-9H-1.3-

ethanoindeno[2.l-c]pyridine HA; C=Z is CH R is CH;,. 7-Cl].

l .2.3 .4.4a.911-hexahydro-2-methyl-6.7-diimethoxy-9H 1 .3-ethanoindeno[2.l ]pyridine [1A;C=Z is CH,. R is 3. M-Zl.

1.2.3 .4.4a.9a-hexahydro- 2-mcthyl-6-methoxy-T chloro-9H-1.3-ethanoindeno[2,lc]pyridine C=Z is CH R is CH G-OCH 7-Cl]. or

l.2.3.4.4a.9a-hexahydro-2.7-dimethyl-9H- l .3-

ethanoindeno[2.1-c]-pyridine HA; C=Z is CH R is 3. =|l- EXAMPLE 8 lS.3R.4aR.9aR)-1.2.3,4.4a.9a-Hexahydro-2-methyl- 9H4 .3-ethanoindeno[2.1-c]pyridine [[A: C=Z is CH R is CH,,. enantiomer of compound of Example 7] was prepared from l S.3R.4aR.9aR)- 1.2.3 .4.4a.9a-hexahydro-Z-methyl- 9H 1 .S-ethanoindenol 2. l -c ]-pyridin-9-one (Example 2) by thioketalization and reduction with Raney nickel according to the procedure of Example 7. It was obtained in the form of its hydrochloride salt. mp. 298C. (dec.). lul =-95.8 1% in H O).

EXAMPLE 9 lR.3S.4aS.9aS)-1.2.3.4.4a9a-Hexahydro-Z-methyl- 9H-1.3-ethanoindeno[2.l-c]pyridin-9-ol [IA; C=Z is CH(OH). R is CH;,].

A solution of 3.13 g. 13 mmol) of( 1R.3S.4aS.9aS]- l.2.3.4.4a.9a-hexahydro-Z-mcthyl-UH-l .3- cthanoindeno[2 l-c]- pyridin-J-one in 50 m1. of cthanol was treated with 1.5 gv (40 mmol) of sodium horohydride in ml. ol'water. The mixture was kept at room temperature for 72 hours. then treated with acetone and more water and ether added. The other layer was dried (anhydrous sodium sulfate) and concentrated to afford a mixture of isomeric alcohols. The latter was subjected to plate chromatography (3:97 isopropylamine-ether; 11 plates; 2 solvent passes) to give 1.8 g. of (lR.3S.4aS.9aS.9S )-l .2.3.4.4a.9a-hexahydro-2- methyl-9H-1.3-ethanoindeon[2.1-clpyridin-9a-ol.

m.p. 98-1( 0C.; hydrochloride salt. m.p. 285287C. (dec.) (from acetonitrile). [01],, =]+62.9 (1'7? in H 0); and 0.25 g. of (1R.3S.4aS.9aS.9R)- 1.2.3.4.4a.9a-hexahydro-2-methy1-9H-1 .3- ethanoindeno[2.l-clpyridin-QB-ol. m.p. l4()- 142C; hydrochloride salt. m.p. 23()-231C. (dec.) (from acetone). [01],, =+74.1 (17: in H O).

By the same procedure. l.2.3,4.4a.9a-hexahydro-2- isopropyl-QH- 1 .3-ethanoindeno[ 2. l -c ]pyridin-9-one. 1.2.3.4.4a,9a-hexahydro-2-methyl-7-chloro-9H-l .3- ethanoindenol2, 1 -c]pyridin-9-one. 1.2.3.4.4a.9ahexahydro-Z-methyl-6.7-dimethoxy-9H- l .3-ethanoindeno[2.1-c]pyridin-Q-one. l.2.3.4.4a.9a-hexahydro-2- methyl-6-methoxy-7-chloro-9H-1.3-ethanoindeno[2.1- clpyridin-9-one. or l.2.3.4.4a.9a-hexahydro-2.7- dimethyl-QH-l .3-ethanoindeno[ 2. l -c ]pyridin-Q-one can be reduced with sodium borohydride to produce. respectively.

l.2.3,4,4a.9a-hexahydro-2isopropy1-9H-1.3- ethanoinden0[ 2. l -c ]pyridin9-ol HA; CH(OH). R is CH(C'H;,)

l.2.3.4.4a.9a-hexahydro-Z-methyl-7-chloro-9H-1.3- ethan0indeno[2.l-c]pyridin-9-ol 11A; C=Z CH(OH). R is CH 7-Cl].

l.2.3.4.4a.9a-hexahydro- 2-methyl-6.7-dimethoxy-9H- l.3-ethanoindeno[2.1-c]pyridin9-ol llA'. C=Z is CH(OH), R is CH 6.7-(OCH; l.

1.2.3 .4.4a.9a-hexahydro-2-methyl-6-methoxy-7- chloro-QH-l .3-ethanoinderio[ 2. l -c ]pyridin-9ol (1A; C=Z is CH(OH). R is CH;,. 6-OC'H;,. 7-Cl]. or

1 .2.3.4.4a.9a-hexahydro-2.7-dimethyl-9H- ethanoindeno[ 2. l c]pyridin-9ol [1A; CH(OH). R is CH 7-CH EXAMPLE 1i) lR.3S,4aS.9R,9aS)-1.2,3,4.4a.9a-Hexahydro-2- methyl-9H-1 .3-ethanoindeno[2. 1 -c]pyridin-9B-ol Acetate [IA; C=Z is CH(OCOCH;;). R is CH lR.3S.4aS.9R.9aS l .2.3.4.4a.9a-Hexahydro-2 methy1-9H-l .3'ethanoindeno[ 2. l -c ]pyridin-QB-ol (Example 9. 10 g., 4 mmol) was treated with 50 m1. of pyri dine and 40 ml. of acetic anhydride for 24 hours at room temperature. The resulting acetate-ester was isolated in the form of its mcthanesulfonate salt (9.48 g.) which when recrystallized from acetone had the m.p. 214215C.. [01],, +197.2 (1'71 in H O).

By replacing the acetic anhydride in the foreging preparation by an acetic anhydride-formic acid mixturc. butyric anhydride. isobutyric anhydride or caproyl chloride. there can be obtained the corresponding formate. butyrate. isobutyrate or caproate esters of l- R.3S.4aS.9R.9aS )-1 .2,3.4.4a.9a-hexahydro-2 methyl- 9H- 1 .3-ethanoindeno[2. 1 -c ]pyridin-9B-ol.

C =Z is EXAMPLE 1 l Diborane Reductions a. A solution of g. (0.38 mol)of(1R.3S.4aS.9aS)- l.2.3.4.4a.9a-hexahydro-2-methyl-9H- l .Ii-ethanoindcno[ 2.l-c]pyridin-9-one in l .0 liters of tetrahydro- "man was added in l.. hours to 1.8 liters of 1M dibo- 'ane in tetrahydrofuran with stirring under nitrogen md cooling by ice. The solution was heated under re-- "lux for 24 hours. and then allowed to stand at room Lernperature for 66 hours. Water 160 ml.) was added lropwise followed by 800 ml. of 2N sodium hydroxide. Vlost of the tetrahydrofuran was boiled away over a 1.5 mm period. Ether was added and the layers were sepaated. The ether solution was dried (sodium sulfate) 1nd concentrated to afford 89.4 g. of an oily residue .hat partially crystallized from pentane. The solid was ligested with ether to afford 37.3 g. of( lR.3S.4aS.9aS 9R l .23.4.4a.9a-hexahydro-Z-methyI- JH-l .3- :thanoindeno| 2.l-cl-pyridin-Qfi-ol. m.p. l38l40(. lhe combined mother liquors were distilled at 1 mm. The fraction boiling at l 16-] 26C. (29.9 g., 40% l was ilmost pure (lR.3S.4aS 9 aSJ- l .2.3.4.4a.9arexahydroQ-methyl-9H-l .B-ethanoindenol 2. l :lpyridine. in, 1.5562. The pot residue crystallized md afforded another 2.4 g. of B-alcohol. m.p. l39-l42C (54 percent yield). The mother liquor obained from this solid (5.l g. l appeared to be a lzl mixurc ofa-alcohol (3 percent yield) and B-alcohol by tlc malysis.

b. By Inverse Addition A solution of l850 ml. of 1M diborane in tetrahydro- 'uran was added over 0.5 hour to 80 g. (0.38 mol) of l R,3S.4aS,9aS l 2.3.4.4aHa-hexahydro-Z-mcthyllH-l.3-ethanoindeno[2.l-c|pyridin-9-one in 940 ml. if tetrahydrofuran with stirring under nitrogen at room emperature. The solution was then heated under relux for 24 hours. and then allowed to stand at room emperature for another 66 hours. The mixture was vorked up as in the preceding experiment. affording 3.l g. of oily residue. Distillation at 0.7 mm. and colection of the fraction that boiled at l ll23C. gave 54.9 g. (73%) of almost pure lR.3S.4aS. 1x3)- .2,3 4,4a.Qa-hexahydro-Z-methyl-QH- l .3- :thanoindenol 2.l-c Ipyridine. A fraction that boiled at 23l40C. solidified. giving l l.7 g. of( lR.3S.4aS.9a- 39R l .2.3,4.4a.9a-hexahydro-2-methyl-)H- l .3- :thanoindenol2.lc]pyridin-9B-ol m.p. l40l42C. lhe pot residue afforded another (v.9 g. of the latter Z-alcohol. mp. l38-l40C. (23% j.

:. Diborane Reduction of a Mixture of a-Alcohol and IS-Alcohol A solution of 9.6 g. of mother liquor from an cxperi' nent like the above under part (a) containing an equal nixture of lR.3S.-laS.9aS)-l.13.4 4a.*)a-hexahydrol-methyl-JH-l .3-ethanoindenol 2, I -c Ipyridin-9B-ol .nd -9a-ol in 160 ml. of tetrahydrofuran was added to 250 ml. of IM diborane in tetrahydrofuran at ice bath EI'HPCHIIUTC. Distillation of the crude product gave 3.6 of lR.3S.4aS.9aS )l .23.4 4a.Ja-hcxahydro-Z- nethyl-QH- l .3-ethanoindenol 2. l -c ]pyridine, b.p.

l5l30C. (0.7 mm.). The pot residue crystallized nd afforded L8 g. of fi-alcohoL mp. l38l40(.

EXAMPLE l2 Diborane reduction of lS.3R.-laR 9aR 1' .2 .3.4.4a.9ahexahydro-Z-methyl-JH- I .3ethanoin enol2.1-c1pyridin-9-one (Example 2] according to he procedure of Example l l (ketone added to dibo ane). afforded lS.3R.4aR.9aR l .2.3.4.4a. a- .exahydro-Lmethyl-QH- l .3ethanoindcnol 2. l

c lpyridine. hp |Z0l 34C. (l-l.5 mm. n

L555]: hydrochloride salt. mp. 298C. (dec.). [01],, 031) I l& in H O). identical with the compound obtained in Example 8: and lS.3R.4aR,9S.9aR)- l.23.4.4a.Ja-hexahydro-Z-methyl-QHl .3 ethanoindeonl 2, l -c lpy ridin-9/3-ol. mp. l38 l 40C.; hydrochloride salt. mp. 220C. (dec. [01],, 74.7 l in water). the cnantiomer of the 9B -ol compound of Example In a similar experiment that was heated under reflux for only three hours. there was also obtained after chromatography some of the isomeric lS.3R.4aR,9R.9aR- I .2.3.4.4a.9a-hcxahydro-2-methyl'9H- l .3- cthanoindeno[ 2, l -c ]pyridin-9o:-ol, hydrochloride salt, m.p. 2R2C.(dec.). [11],, fi2.fi (1'71 in H O). the enantiomer of the )a-ol compound of Example 9.

A mixture of the enantiomeric )aand Mi-alcohols was also prepared by hydrogenation of a solution of 0.59 g. (2.6 mmols) of( lS.3R.4aR,9aR)-l .2,3.4,4a.9ahexahydro-Q-methyl-9H- l .3-ethanoindenol 2. l c Ipyridin-J-one (Example 2) in 300 ml. of 957: ethanol containing 0.25 g. of platinum oxide catalyst (pressure 3.5 kg/cm"). The catalyst and solvent were removed to give 059 g. of an epimeric mixture of alcohols which was separated by plate chromatography (97:3 etherisopropylamine The less polar band afforded mg. (25% of BB-ol compound. m.p. l28l 35C.; and the more polar band gave 290 mg. (49%) of 3a-ol compound. m.p. 99]00C.

EXAMPLE l3 Diborane reduction of lR.3S.4aS.9aS l.13.4.4a.9a-hexahydro-Z-methyl-7-fluoro9H- l .3- ethanoindenolll-clpyridin-Q-one Example 3) by the method described in Example l l. and distillation of the crude mixture gave lR.3S.4aS.9aS)-l .2.3.4,4a 9ahexahydro-2-methylJ-fluoro-QH- l .3-ethanoindeno- {Z.l-c]pyridine llA; R is CH (=2 is CH 7F]. b.p. l25l30C. (0.7 mm.) mp. 5l54.5C.; hydrochloride salt. m.p. Z9lC (dee) (from acetonitrile), [a],, =+83.4( W in H 0) (74 percent yield); and lR.3S.- 4aS 9R.9aS I 2,3.4,4a.9a-hexahydro-Z-methyl-7- fluoro-JH- l .3-ethanoindenol 2. l -c lpyridin-QB-ol HA; R is CH (=2 is CHrOH). 7F]. b.p. l30-l47C. (0.7 mm.) m.p. ll4l l5(. (from ether); hydrochloride salt. mp. 268-270C. (dec.). [01],, +83.4 l7( in H 0) (26 percent yield).

EXAMPLE l4 lR.3S.4aS.9R.9aS l .23.4.4a.9a-Hexahydro-2- methyl-7-fluoro-9H-l .3-cthanoindenol 2. l -c ]pyridin- )fi-ol Acetate llA; R is CH (=2 is CH(OCOCH 7F] was prepared by acetylation of the 913-0] compound of Example l3 according to the procedure of Example 10. and was obtained in 86 percent yield. m.p. l28-l 29(. (from pcntane). lul +59.3 1% in CHCM).

EXAMPLE l5 Diborane reduction of lR.3S.4aS.9aS)- l .13.4.4afla-hexahydro 2-methyl7methoxy-9H- l .3- ethanoindenol2.l-c]pyridin-9-one (Example 4) according to the procedure of Example 1 I gave a mixture which was chromatographcd on silica gel (40 g. per g. of product mixture) that had been treated with isopropylamine l ml. per 4 g.) prior to packing. Elution of the column with lzl cthenpentane gave a 707: yield of lR.3S.'-laS. )aS l .23.4.-4a.Ua-hexahydro-2- methyl7-methoxy-9H- l .3-ethanoindenol 2. l -c pyridine llA; R is CH; C=Z is CH- 7-OCH; p-toluenesulfonate salt. m.p. 275C (dce) (colorless. thin plates from absolute ethanol). [01],, I +49.2 l)? in H O Further elution of the column with the same solvent mixture brought out a 2()/( yield of lR.3S.4aS. 9R .9aS l .2.3 .4.411.Qa-hexahydro-2-methyl-7- methoxy-9H-l 3-cthanoindeno[ 2. I -c lpyridin-JB-ol llA; R is CH C 7. is CH(OH). 7-OCH:;l; hydrochloride salt. m.p. 275C. (deel (from absolute ethanol). lul +269 l"? in H O).

EXAMPLE lo Diborane reduction of lR.3S.4aS.9as)- l.2.3.4.4a. lahexahydro-2-mcthyl-fi-methoxy-QHl .3- cthanoindenol2.l-clpyridin-J-one (Example according to the procedure of Example 1 I gave as the sole product in 74% yield (lR.3S.4aS.9aS)- l.2.3 .4.4a.9a-hexahydro-2-methyl-bmtethoxy-JH- l .3- ethanoindenol2.l-clpyridine [[A; R is CH 2 is CH o-OCH l; sulfate salt. m.p. l95l97C. (dee) (from acctonitrile). l01|,, +93.7 l'/( in H O).

EXAMPLE l7 Diborane reduction of lR.3S.4aS.9aS)- l .2.3.4 4a.9a-hexahydro-2-methyl-8-mcthoxy-9H- l .3- cthanoindenol 2.l-clpyridin-Q-one (Example 5) according to the procedure of Example l I, gave a product which was chromatographed on silica gel (80 g. per g. product) using ether-pentaneisopropylamine(70:29:l) for elution. There was obtained in 86' yield (lR.3S.4aS.9aS)-l .2.3.4.4a.9ahexahydro-Z-methyl-X-methoxy-JH-1,3- cthanoindeno[2.l-clpyridine [lA; R is CH K-OCH I; p-toluenesulfonate salt. m.p. l47.5l5lC. (needles from absolute ethanol) and m.p. l33l 35C. (massive prisms from water). [01],? +4().2 I)? in H O).

EXAMPLE 1% Reduction otlB (C=7. is C=O. R is CH with Diborane A solution of 3[).(1g.(().l25 mol of( lR.3S.4aR. l ()a- R l .3.4.4a.5. ltJa-hexahydro-2-methyll .3- ethanoben7.[glisoquinolin-ltl(2H)-one in 500 ml. tetrahydrofuran was added dropwise with stirring to 750 ml, of IM diborane in tetrahydrofuran under nitrogen at S-IUC in minutes. The solution was refluxed for )6 hours. quenched with 60 ml. water. treated with 300 ml. of 2N sodium hydroxide and refluxed for 2 hours. The tetrahydrofuran was boiled out on a steam bath. and the residual mixture was saturated With sodium chloride and extracted 3 times with ether. The extracts were concentrated to give a pasty residue which was triturated twice with pentane 150 ml. The solid. 17.7 g. of m.p. IMP-145C. was recrystallized from acctonitrile to give [12 g. of (lR.3S.4aR.lUS.lllaR)- l 1.3.4.4115 l U. l ()a-octahydro-Z-methyl-l .3- ethanobcnzIglisoquinolin-Illa-o] llB; C=Z is CH(OH- a). R is CH;.]. prisms. m.p. lh6l68C. (possible transformation at l28l 32C. lts hydrochloride salt was obtained in the form of prisms from ethanol. m.p. 328C. (dec.). [01,, I -37.o lkr in H O).

The pentane triturate above. from which the latter product separated, contained l l.4 g. of an oily mixture ol products. Column chromatography on 450 g. ol silica gel using ethenpentane mixtures for elution failed to give separation. The 7.9 g, of oil recovered from the column was chromatographed on 24 prep silica plates (2() X 40-cm) (3:97 isopropylamine-ether) to give 3 major products.

The least polar band afforded l.6 g. of( lR.3S.4aR. l ()aS l .2.3 .4 4a.5. l O. l()a-octahydro-Z-methyl-l .3- ethanobenzlglisoquinoline [18; C=Z is CH R is CH cis form]. m.p. 83 85C. Its hydrochloride salt was obtained in the form of needles from acetone. m.p. 294295C. (dec.). [01],, +44.l l7r in H O).

The band of intermediate polarity furnished 2.1 g. of ben2[g]isoquinolin-lUB-ol llB; C=Z is CH(OH-B). R is (H-,1. m.p. l38l45C. One recrystallization from hexane gave a sample with m.p. l49l5 lC. (prisms from hexane); [11],, 39.5 (1% in CHCl The most polar band (2.1 g. of oil) had to be rechromatographed on 8 prep plates using 3 passes of the same solvent system. Thus was obtained l .8 g. of( lR.- 3S.4aR. l ()aR )-l .2.3.4.4a.5. ll), 1 ()a-octahydro-2 methyl-l.3-ethanobenz[glisoquinoline llB; C=Z CH R is CH;,, trans form] which formed a crystalline hydrochloride salt. m.p. 3(l23()3C. (dec.) (prisms from ethanol); l d F +42.l) (1% in H O).

The configurations of the cis and trans bases llB; C=Z is CH R is CH were assigned from the fact that the cis base only produced a 17! yield of quaternary salt with ethyl iodide. whereas the trans base gave 4W? of quaternary salt.

By analogous procedures lR.3S.4aR.l(laR)- l .3.4.4a.5. l ()a-hexahydro-Z-methyl-S-fluorol .3- ethanobenzlglisoquinolin-l()( 2H )-one. (lR.3S.4aR.l- Oak )-1 .3.4.4a.5. l ()a-hexahydro-2-methyl-8-chloro- 1.3-ethanobenzlglisoquinolinl t)( 2H )-one. lR.3S.4a- R, l ()aR )-l ,3.4,4a.5. l ()a-hexahydro-Z-methyl-8- methoxyl .3-ethanobenzlgl-isoquinolinl 2H )-one or (lR,3S 4aR,lUaR)l.3.4.4a.5.ll)a-hexahydro-2.8- dimethyll .3-ethanobenzlg]isoquinolinl 2H )-one can be reduced with diborane to produce mixtures of the corresponding 9-ol and 9-cleoxy compounds.

EXAMPLE [9 cthanobenzlg]isoquinoline can be demethylated to produce lR.3S.4aR. l()aR )l .3.4.4a.5. l ()a-hexahydro' Z-methyl-l.3-ethanobenzlglisoquinolin-Sml 11B; R is CH;,. C 7. is CH 8-OH l.

EXAMPLE 10 Ethyl [lR.3S.4aS.9aSj-l .2.3.4.4a.9a-hexahydro-9H- l .3- ethanoindeno[2.l-clpyridineZ-carhoxylate llA; R is C H,-,OCO. C=Z is CH A mixture of 0.1 mol of (lR.3S,4aS. )aS)- l.2.3.4.4a,9a-hexahydro-2-methyl-9H- l .3- :thanoindeno[2.l-c]pyridine (Example 7) and 0.2 mol )f ethyl chloroformate was warmed on a steam hath intil evolution of methyl chloride ceased. An addiional 0.2 mol of ethyl chloroformate was added and he mixture was heated under reflux for 4 hours. The nixture was cooled. diluted with ether. washed with 2N iydrochloric acid. concentrated. and distilled to give in 77.571 yield ethyl (lR.3S.4aS.9aS)-l.2.3.4.4a.9a texahydro-QH-l .3-ethanoindenol 2. l -c lpyridine-Q- :arhoxylate. b.p. lS2l 60C. (0.7 mm. a 1.549l. vhich crystallized and melted at 88-90C. (from penane).

By an analogous procedure (1R,3S.4aR.l0aS)- l .23 .4.4a5. 10. l ()a-octahydro-Z-methyl-l .3- :thanohenziglisoquinoline (Example 18) can be conrerted to ethyl (lR,3S.4aR. l0aS) l .2.3,4.4a.5.l0.l0avctahydro-Z-methyl-l .3-ethanohenzig]isoquinoline-Z- :arhoxylate [03; R is C- H OCO. C=Z is CH EXAMPLE 21 A mixture of ethyl (lR.3S.4aS.9aS)-l.2.3.4.4a.9aiexahydro-JH-l .3-ethanoindeno{ 2. l c lpyridine-Z- :arhoxylate (Example and 6N hydrochloric acid 20 ml. per g.) was heated under reflux for 48 hours. 1-Propyl alcohol (8 ml. per g.) was added and reflux :ontinued for 24 hours. Ether was added and the prod- .lct extracted with 2N hydrochloric acid. The acidic ex- :racts afforded in 80% yield the hydrochloride salt of f lR.3S.4aS.9aS)-l .2.3.4.411.Ja-hexahydro-QH-l .3- :thanoindeno[2.l-clpyridine. ni.p. 303C. (deej (from acetonitrile). [01],, +881? (1'7: in H O).

By an analogous procedure, ethyl lR.3S.4aR.I0aS l.2.3.4,4a,5. l 0. l ()a-octahydro-Z-methyll .3- :thanohenzlglisoquinoline-Z-carhoxylate can he con.- v'L'IICd to (lR.3S.4aR. l 0aS)- l 1.3.4.421. l 0,l0a Jctahydro-l,3-ethanohenzlglisoquinoline LIB; R is H. C=Z is CH EXAMPLE 2?.

(lR.3S.4aS.9aS J-ZCyclopropylcarbonyll .2.3.4.4a.)a-hexahydro-9Hl .3-ethanoindeno[ 2.1- clpyridine [lA; R is cyclopropyl-CO. C=Z is CH.

Cyclopropanecarhoxylic acid chloride (5.25 g, 1050 mol) was added dropwise to 10.0 g. (0.050 mol) )f (lR,3S.4aS.9aS)- l .2.3,4.4aHa-hexahydro-QH l .3- :thanoindeno[2.l-clpyridine (Example Zl in I00 ml. at chloroform containing 5.1 g. (0.050 mol) of triethyl- Amine. The mixture was heated under reflux for IS ninutes, cooled. and washed with 2N sodium hydroxde. 2N hydrochloric acid and brine. The extracts were dried over anhydrous sodium sulfate and concentrated :o give lR.3S.-'1aS.9aS )-Z-cyclopropylcarlionyll.23.4.4a.Ja-hexahydroHH- l .B-cthanoindcnoI 2, l :Ipyridine. used directly in Example 23 without further nurification.

By an analogous procedure l.2.3,4.4a.-5. l 0. l (Ja'octah drol .3-

cthanohenzlgjisoquinoline can he converted to lR.3- S.4aR. l 0aS )-2-cy clopropylcarbonyll 2.3.4.4115 l0.l0a-octahydro-l.3-ethanohen2lgIisoquinoline HE; R is cyclopropyl-CO. C=Z is CH EXAMPLE 23 lR.3S.4aS.9aS )-Z-Cyclopropylmethyl-l .2.3.4.4a.9ahexahydro-QH-l .B-ethanoindenol2.l-c]pyridine HA; R is cyclopropyl-CH C=Z is CH The total crude product from Example 22 was dissolved in I00 ml. of tetrahydrofuran and added to 5 g. of lithium aluminum hydride in 400 ml. of tetrahydrofuran. The mixture was heated under reflux for 5 hours. quenched with 10 ml. of water and filtered. The filtrate was concentrated and the free base product converted to the hydrochloride salt of lR.3S.4aS.9aS)-2- cyclopropylmethyll .2.3,4,4a.9a-hexahydro-9H- l .3- ethanoindeno-[2.l-c]pyridine. colorless needles. m.p. 239-240C.. [01],, +85.6 (1'7? in H 0) percent yield).

By an analogous procedure. lR.3S.4aR.l0aS)-2- cyclopropylcarbonyl-l ,2.3.4.4a.5. l 0. l [)a-octahydrol.3-ethanohenz[gl-isoquinoline can be converted to lR.3S,4aR. l 0aS )'Z-cyclopropylmethyll2.3.4.4115.l0.l0a octahydro-L3 cthanohemlglisoquinoline HE". R is cyclopropyl-CH- (=2 is CH.

EXAMPLE 24 lR.3S.4aS,9aS )-Z-Benzyll .2.3.4.4a.9a hexahydro- 9H-l.3-ethanoindeno[2.lc]pyridine (IA; R is (IH CH C=Z is CH was prepared by reacting lR.- 3S.4aS.9aS l .2.3.4.4a.9a-hexahydro-QH- l .3 ethanoindenol2.l-c]pyridine (Example 21) with hen- 7oyl chloride and reducing the resulting N-henzoyl compound with lithium aluminum hydride according to the procedures of Examples 2'. and 23. The product was obtained in the form of its p-toluenesulfonate salt. mp. 206-207C. and 217-2 19C.. [01],, I +980 l /z in ethanol By an analogous procedure. 1.2.3.4,-4a.5. l 0. lUa-octahydrol .3- ethanohenzlglisoquinoline can be converted to IR.3 S.laR. lUaS 2 hen7yl'l 1.3.4.4215 l 0. l [)a-octahydrol.3-ethanohen2lglisoquinoline HE. R is C..H -,CH- C 2 is CH EXAMPLE 25 lR.3S.4aS.9aS)-l.13.4.4a.Ja-Hexahydro-Z- hydroxycthyl- JH- l .3-cthanoindenol 2. l -c lpyridine (1A; R is HOCH CH C 7. is CH A mixture of).63 g. (0.043 mol) ot( lR.3S.4aS,9aS- l .12.].4.4a.9a-hexahydro-9H- l .3-ethanoindeno[ 2. l clpyridine (Example 21). 6.96 g. (0.082 mol) of sodium bicarbonate. 7.1 g. (0.047 mol) ofethylene bromohydrin and 50 ml. of methanol was stirred at room temperature for 9r hours. Ether was added. the mixture was filtered and the filtrate washed with brine. dried over anhydrous sodium sulfate and concentrated to give 72 g. of (lR.3S.4aS.9aS)l.2.3.4.-la.9ahexahydro-Z-hydroxy ethyl-9H l .3-ethanoindenol 2. l clpyridine; hydrochloride salt. colorless needles. m.p. 23023ZC [alfi +8lA lw' in H O).

By an analogous procedure. lR.3S.-laR.l0aSl l .2.3.-1.4a.5.l0.ltla-octahydro-l .3 cthanohcnzlglisoquinoline can he converted to I lR.3

S.4aR.l ()aS )-2-hydroxycthyl-l .2.3.4.4a.5. I l). l ()aoctahydro-l .3-ethanobcnzlglisoquinoline HE; R is HOCH CI-L, C=Z is CH EXAMPLE 26 (lR,3S)-l .23.4-Tetrahydro-l-mcthyl-9H- l .3- ethanoindenol 2.1 -c l-pyridinc A mixture of 26.4 g. (1H2 mol) of( lR.3S.4aS.)aS.9 R l .23 .4,4a.9a-hexahydro-2-methyl-9H- l .3- ethanoindeno[2.l-cl-pyridin-QB-ol and lSU ml. of phosphorus oxychloride was heated at reflux for 3 hours. The excess reagent was removed by heating the mixture in vacuo. The oily residue containing the delta- ).9a compound was dissolved in methanol and treated with 2.5 g. of sodium methoxide. The mixture was heated under reflux for l.5 hours and filtered free of sodium chloride. The filtrate was diluted with ether, washed with saturated sodium chloride. dried over. anhydrous sodium sulfate and concentrated to give 20.0 g. of product. Distillation at l l2l 16C. (0.5-0.6 mm.) yielded 18.0 g. (7471) of (lR.3S)-l.2.3.4- tetrahydro-Z-methyl-QH- l .3-ethanoindeno-l 2. l c]pyridine; hydrochloride salt. m.p. 2t)82'/'()Cv (from acetone). [01],, +8().7 (l 7: in H O).

EXAMPLE 27 (lR.3S.4aR.9aR )-l .2.3.4.4a.9a-Hexahydro-Z-methyl- )H-l .3-ethanoindeno[2.l-c]pyridine [[A; R is CH C=Z is CH cis-anti configuration] A solution of 5.0 g. (0.02 mol) of the hydrochloride salt ollR.3S)-l 2.3,4-tetrahydro-2-methyl-9H-l .3- ethanoindeno-[ll-c]pyridine (Example 26) in 300 ml. of 957: ethanol was hydrogenated at 3.5 kg/cm in the presence of 0.5 g. of NW: palladium-on-carbon catalyst. When one mol of H was absorbed. the catalyst and solvent were removed. The crystalline residue (5.0 g.) was recrystallized from acetone to give 4.0 g. (80% of lR.3S.4aR.9aR)-l.13.4.4a9a-hexahydro-2- methyl-9H-l,3-ethan0indeno[2.l-c]pyridine in the form of its hydrochloride salt. m.p. 306C. (dec. )1 [01],? -27.9 V7: in H O).

Similar hydrogenation of the isomeric delta-9.9a compound prior to its rearrangement with base afforded l R,3S.4aS.9aS l .2.3 .4.4a.9ahexahydro-2- methyl-9H- l .3-ethanoindenol 2, l -c ]pyridine having the cissyn configuration, identical with the compound obtained in Example ll(a).

The cis-anti isomer readily formed an ethiodide quaternary salt whereas the cis-syn isomer did not react with ethyl iodide.

We claim:

1. A compound selected from the group consisting of (A) a compound of the formula wherein:

R is hydrogen. lowcr-alkyl. lowenalkanoyl. loweralkoxycarboirvl. cycloalkylcarbonyl. cycloalkyllower-alkyl. phcnyllowcr-alkyl or hydroxy-lowcralkyl. c cloalk \l. each instance. having from three (wl l to six ring members and a total carbon content of from three to ten carbon atoms;

( 7 is C=O. CH CH(OH) alkanoyl n is (l or I;

and the phenyl ring is unsubstituted or substituted by from one to two substituents selected from the group consisting of lower-alkyl. lower-alkoxy. fluoro. chloro and hydroxy; and (B) a medicinally acceptable acid-addition salt of a compound under (A) abovev 2. A compound according to claim I wherein R is methyl. C=Z is C=O and n is t).

3. l .2.3,4.4a,9a-Hexahydro-2-methyl-9H- l .3- ethanoindeno[2.lclpyridin-Q-one. according to claim 2.

4. l.2.3.4.4a,9a-Hexahydro-Z-methyl-6-methoxy- 9H-l .3-ethanoindeno[ 2. 1 -c ]pyridin-9one according to claim 2.

5. l.2.3.4.4a,9a-Hexahydro-2-methyl7-fluoro 9H- l,3-ethanoindenol2.l-c]pyridin-9-one. according to claim 2.

6. 9H- l .3-ethanoindeno[ 2. l -c lpyridin-Q-one. to claim 2.

7. A compound according to claim 1 wherein R is methyl. C=Z is CH(OH) and n is l).

8. l.2.3.4.4a.9a-Hexahydro2-methyl-9H- l .3- ethanoindenol'l.l-c]pyridin-9-ol. according to claim 7.

9. l2.3.4.4a.9aHexahydro-Z-methyl-7-t'luoro-9H- l.3-ethanoindeno[2.l-c]pyridin-9-ol. according to claim 7.

l0. l.23.4.4a.9a-Hexahydro-2-methyl-7-methoxy- )H-l .3-ethanoindenol 2. l -c lpyridin-Q-ol. according to claim 7.

11. A compound according to claim I wherein R is methyl. C=Z is CH(O-lower-alkanoyll and n is 0.

l2. l2.3.4.4a.9a-Hexahydro-Z-methyl-QH- l .3- ethanoindenol2.1-clpyridin-9-ol acetate. according to claim ll.

I3. l.2.3,4.4a.9a-HexahydroQ-methylJ-fluoro-9H- l.3-ethanoindeno[2.l-c]pyridin-9-ol acetate. according to claim ll.

14. A compound according to claim I wherein R is methyl. C=Z is CH: and n is 0.

l5. l.2.3.4.4a.9a-Hexahydro-2-methyl-9H-l .3- cthanoindenolll-c]pyridine. according to claim l4.

l6. l.23.4.4a.9a-Hexahydro-Z-methyl-fi-methoxy- 9H-l.3-ethanoindenol2.l-c]pyridine, according to claim l4.

l7. l.2.3.4.4a,9a-Hexahydro-2-methyl-o-hydroxy- 9H- 1 .3-ethanoindeno[ 2. l -c lpyridine. according to claim l4.

l8. l.23,4.4a.9a-Hexahydro-Q-methyl-7-fluoro-9H l.3-ethanoindenol2.l-c]pyridine. according to claim 14.

or CH( O-lowerl.2.3.4.4a.9a-HexahydroJ-methyl-X-methoxyaccording denol2.l-c I-pyridine. according to claim 1.

22. l.2.3.4.4a.9a-Hcxahydro-Z-cyclopropylmethyl )H-[.3-cthanoindcnol2.1-clpyridine. according to claim I.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,901,892

DATED August 26, 1975 lNvENTOktS) 1 Robert L. Clarke and 501 J. Daum It is certified that error appears in the aboveidentitied patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 21, "lower-alkoxy" should read --lower-alkanoyl--.

Column 20, line 5, Claim 29, "l,2,3,4,4a,l0,l0a" should read --l,2,3,4,4a,5,10,l0a--.

Signed and Scaled this eighteenth D3) Of November 1975 [SEAL] A nest:

RUTH C. MASON C. MARSHALL DANN -1rrvslrng ()fjrrer (mmmssimwr n] Pau'ms and Trademarks 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 wherein R is methyl, C Z is C O and n is
 0. 3. 1,2,3,4,4a,9a-Hexahydro-2-methyl-9H-1,3-ethanoindeno(2, 1c)pyridin-9-one, according to claim
 2. 4. 1,2,3,4,4a,9a-Hexahydro-2-methyl-6-methoxy-9H-1,3-ethanoindeno(2,1-c)pyridin-9-one according to claim
 2. 5. 1,2,3,4,4a,9a-Hexahydro-2-methyl-7-fluoro-9H-1,3-ethanoindeno(2,1-c)pyridin -9-one, according to claim
 2. 6. 1,2,3,4,4a,9a-Hexahydro-2-methyl-8-methoxy-9H-1,3-ethanoindeno(2,1-c)pyridin-9-one, according to claim
 2. 7. A compound according to claim 1 wherein R is methyl, C Z is CH(OH) and n is
 0. 8. 1,2,3,4,4a,9a-Hexahydro2-methyl-9H-1,3-ethanoindeno(2,1-c)pyridin-9-ol, according to claim
 7. 9. 1,2,3,4,4a,9a-Hexahydro-2-methyl-7-fluoro-9H-1,3-ethanoindeno(2,1-c)pyridin -9-ol, according to claim
 7. 10. 1,2,3,4,4a,9a-Hexahydro-2-methyl-7-methoxy-9H-1,3-ethanoindeno(2,1-c)pyridin-9-ol, according to claim
 7. 11. A compound according to claim 1 wherein R is methyl, C Z is CH(O-lower-alkanoyl) and n is
 0. 12. 1,2,3,4,4a,9a-Hexahydro-2-methyl-9H-1,3-ethanoindeno(2,1-c)pyridin-9-ol acetate, according to claim
 11. 13. 1,2,3,4,4a,9a-Hexahydro-2-methyl-7-fluoro-9H-1,3-ethanoindeno(2,1-c)pyridin -9-ol acetate, according to claim
 11. 14. A compound according to claim 1 wherein R is methyl, C Z is CH2 and n is
 0. 15. 1,2,3,4,4a,9a-Hexahydro-2-methyl-9H-1,3-ethanoindeno(2,1-c)pyridine, according to claim
 14. 16. 1,2,3,4,4a,9a-Hexahydro-2-methyl-6-methoxy-9H-1,3-ethanoindeno(2,1 -c)pyridine, according to claim
 14. 17. 1,2,3,4,4a,9a-Hexahydro-2-methyl-6-hydroxy-9H-1,3-ethanoindeno(2,1 -c)pyridine, according to claim
 14. 18. 1,2,3,4,4a,9a-Hexahydro-2-methyl-7-fluoro-9H-1,3-ethanoindeno(2,1 -c)pyridine, according to claim
 14. 19. 1,2,3,4,4a,9a-Hexahydro-2-methyl-8-methoxy-9H-1,3-ethanoindeno(2,1 -c)pyridine, according to claim
 14. 20. 1,2,3,4,4a,9a-Hexahydro-2-methyl-7-methoxy-9H1,3-ethanoindeno(2,1 -c)pyridine, according to claim
 14. 21. 1,2,3,4,4a,9a-Hexahydro-9H-1,3-ethanoindeno(2,1-c)-pyridine, according to claim
 1. 22. 1,2,3,4,4a,9a-Hexahydro-2-cyclopropylmethyl-9H-1,3-ethanoindeno(2,1 -c)pyridine, according to claim
 1. 23. 1,2,3,4,4a,9a-Hexahydro-2-(2-hydroxyethyl)-9H-1,3-ethanoindeno(2,1 -c)pyridine, according to claim
 1. 24. 1,2,3,4,4a,9a-Hexahydro-2-benzyl-9H-1,3-ethanoindeno(2,1-c)pyridine, according to claim
 1. 25. 1,2,3,4,4a,9a-Hexahydro-2-carbethoxy-9H-1,3-ethanoindeno(2, 1-c)pyridine, according to claim
 1. 26. 1,2,3,4-Tetrahydro-2-methyl-9H-1,3-ethanoindeno-(2,1-c)pyridine.
 27. A compound according to claim 1 in which R is methyl and n is
 1. 28. 1,3,4,4a,5,10a-Hexahydro-2-methyl-1,3-ethanobenz(g)isoquinolin-10(2H)-one, according to claim
 27. 29. 1,2,3,4,4a,10,10a-Octahydro-2-methyl-1,3-ethanobenz(g)isoquinoline, according to claim
 27. 30. 1,2,3,4,4a,5,10,10a-Octahydro-2-methyl-1,3-ethanobenz(g)isoquinolin-10-ol, according to claim
 27. 